Emerging treatment options for prostate cancer

Abstract

Introduction:

Prostate cancer treatment has rapidly evolved in the past few years. Androgen deprivation therapy has been the backbone of treatment for locally advanced and metastatic prostate cancer, but incremental benefits in survival have been shown by adding androgen-receptor pathway inhibitors (ARPI) across various spectrums of disease state. In addition, docetaxel chemotherapy remains the first-line chemotherapy regimen available with survival benefits shown with triplet therapy in those who are chemotherapy eligible. However, disease progression remains inevitable and novel agents such as radioligand therapy with lutetium have shown improvement in survival.

Areas covered:

This review discusses the pivotal trials that led to the U.S. FDA approval of agents utilized in metastatic prostate cancer and explores the use of novel agents including prostate-specific membrane antigen-targeting agents, radioligands, cell-based therapy, chimeric antigen receptor T-cell, BiTE, and antibody drug conjugates.

Expert opinion:

Treatment landscape for metastatic castrate-resistant prostate cancer (mCRPC) has evolved beyond additional agents with ARPI and/or docetaxel, including other treatments with sipuleucel-T, radium, cabazitaxel, PARP inhibitors, and lutetium, which have specific indications and roles in sequencing. Novel therapies remain critically needed after progression from lutetium.

1. Introduction

Prostate cancer remains the most common non-cutaneous malignancy among American men. It is estimated to occur in 268,490 men and expected to result in 34,500 deaths in 2022 [1]. A review of over 3 million prostate cancer diagnoses from 2001 to 2017 revealed approximately 5% of new cases to be metastatic at diagnosis with 5- and 10-year survivals of around 30% and 18%, respectively [2]. In addition, of patients definitively treated for localized prostate cancer, 20–30% will have recurrence in the form of rising prostate-specific antigen (PSA) or disseminated disease that necessitates further treatment [3]. The original backbone for treatment of metastatic prostate cancer, androgen ablation or androgen deprivation therapy (ADT), was discovered in the 1940s [4]. Since then, the treatment landscape has evolved substantially. Many new FDA-approved therapies within the past decade have been oriented around the androgen receptor; however, multiple novel avenues of treatment have emerged, demonstrating promise for expansion of the therapeutic tools available to treat this lethal disease.

2. Current treatment landscape

The current treatment landscape for metastatic prostate cancer includes chemotherapy, anti-androgens, radiopharmaceutical therapy, immunotherapy, and targeted therapies. The mainstay chemotherapies used in metastatic prostate cancer are docetaxel and cabazitaxel, both used in combination with ADT. In patients with metastatic castration-resistant prostate cancer (mCRPC), docetaxel plus prednisone improved median overall survival (OS) compared to mitoxantrone plus prednisone in the randomized phase III study TAX 327 (18.9 months vs. 16.5 months) [5]. Docetaxel’s benefit when added to ADT in metastatic castration-sensitive prostate cancer (mCSPC) was demonstrated in two studies: CHAARTED and an arm of the multiplatform study, STAMPEDE [6,7]. The first of these studies yielded an improved OS of 57.6 months when docetaxel was added to ADT versus 44.0 months with ADT alone. Patients with mCSPC treated in the ADT plus docetaxel arm of STAMPEDE had a median OS of 81 months while those given ADT alone had a median OS of 71 months. Cabazitaxel only carries an approval in mCRPC. When used with prednisone in mCRPC patients who had progressed on docetaxel, it had a 2.4-month improvement in OS over mCRPC patients treated with mitoxantrone plus prednisone [8]. It has also been shown to improve survival in patients with mCRPC post-docetaxel and have received either abiraterone or enzalutamide, compared to switching to the other of abiraterone or enzalutamide in the CARD trial: median OS 13.6 versus 11.0 months (HR 0.64; 95% CI, 0.46–0.89) [9].

Androgen receptor pathway inhibitors (ARPI) with indications for treatment of prostate cancer include the androgen synthesis inhibitor, abiraterone, and the three androgen receptor inhibitors: enzalutamide, apalutamide, and darolutamide. Abiraterone in combination with low-dose prednisone was first shown to improve OS in mCRPC post-docetaxel in the study COU-AA-301 [10,11]. Here, median OS was 15.8 months with abiraterone plus low-dose prednisone compared to 11.2 months for placebo. A subsequent study of pre-docetaxel patients (COU-AA-302) showed improved median OS favoring those treated with abiraterone-prednisone over patients treated with prednisone monotherapy (not reached vs. 27.2 months) [12]. Enzalutamide’s efficacy in mCRPC was shown as it improved median OS compared to placebo in post-chemotherapy mCRPC patients (18.4 months vs. 13.6 months) [13] and then in the pre-chemotherapy mCRPC setting where there was a radiographic progression-free survival (rPFS) and OS benefit in the enzalutamide group compared to placebo [14].

In non-metastatic CRPC (nmCRPC), apalutamide, enzalutamide, and darolutamide have all been shown to improve metastasis-free survival as the primary endpoint. The SPARTAN, PROSPER, and ARAMIS trials provided the support for approval of apalutamide, enzalutamide, and darolutamide, respectively, in nmCRPC, specifically in patients with PSA doubling times of ≤10 months [15–17]. All three registrational studies demonstrated significant improvements in OS as secondary endpoints.

ARPIs have also been widely adopted in mCSPC. Abiraterone with prednisone added to ADT improved OS in two separate randomized studies: LATITUDE and an arm of the STAMPEDE trial [18,19]. In LATITUDE, the median OS was not reached for the abiraterone group compared to 14.8 months in the placebo group. The STAMPEDE study showed fewer deaths in the ADT plus abiraterone group compared to ADT alone: 184 versus 262 (HR 0.63; 95% CI, 0.52–0.76, P < 0.001). The ENZAMET trial showed OS improvement in the enzalutamide plus standard of care (SOC) arm compared to the SOC arm (5-year OS 67% vs. 57%, HR 0.7; 95% CI, 0.58–0.84), with docetaxel allowed as SOC [20,21]. Apalutamide with ADT also yielded an OS advantage compared to ADT alone, with median OS not reached versus 52.2 months (HR 0.65, p < 0.0001) in the TITAN trial [22,23]. In the last year, the needle has moved further for mCSPC treatment, with data supporting the use of ARPIs in combination with docetaxel and ADT, termed triplet therapy. In the ARASENS trial, the addition of darolutamide compared to placebo to docetaxel and ADT improved OS by an HR of 0.68; 95% CI, 0.57–0.80 [24]. Similarly, the addition of abiraterone with prednisone (vs. placebo) to docetaxel and ADT in the PEACE-1 trial improved OS (HR 0.82, 95% CI, 0.69–0.98) [25].

Radiopharmaceutical therapy has largely been composed of the alpha emitter Radium 223 dichloride. Radium 223 dichloride was the first-in-class alpha-emitting particle that showed improvement in OS in the treatment of mCRPC based on the ALSYMPCA trial [26]. Currently, Radium 223 dichloride is utilized in mCRPC patients with symptomatic bone metastases. Beta emitters have been used in mCRPC for many years in the form of samarium-153 and strontium-89. However, their role had only been in palliation for painful bone metastases as neither provided survival benefit [27,28]. The most recent advancement in radioligand therapy has been with beta emitters, specifically lutetium-177 (177Lu), which has been combined with prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein specifically expressed in prostate cancer cells. TheraP, a phase II study that compared 177Lu-PSMA-617 to cabazitaxel in patients with mCRPC, showed a higher percentage of patients with PSA responses (defined as reductions of at least 50% from baseline) in the lutetium-treated group [29]. This suggested that 177Lu-PSMA-617 may have a role as an alternative to cabazitaxel in mCRPC. Adverse events (AEs) of particular interest in this study include dry mouth, dry eyes, diarrhea, thrombocytopenia, and neuropathy. Dry mouth and dry eyes were seen in 60% and 30% of the patients treated with lutetium as compared to 21% and 4%, respectively, of patients treated with cabazitaxel. This was all grade 1–2 with no grade 3–4 events seen for either treatment with regard to these AEs. Diarrhea was seen in approximately triple the percentage of patients receiving cabazitaxel as compared to lutetium, but again this was mostly grade 1–2. Thrombocytopenia was not only more frequent in lutetium but also more severe as 11% of patients treated with lutetium experienced this at grade 3–4 compared to none of the patients treated with cabazitaxel. Neuropathy, a known possible AE of taxane chemotherapy, occurred in 26% of patients treated with cabazitaxel as compared to lutetium, which is important in a population that may have residual neuropathy from prior taxane treatment. The phase III VISION trial enrolled patients with mCRPC after failure from at least one prior ARPI and one taxane treatment and compared 177Lu-PSMA-617 to SOC therapy. The improvement in OS in the 177Lu-PSMA-617 arm (median OS 15.3 vs. 11.3 months, HR 0.62, 95% CI, 0.52–0.74) led to U.S. FDA approval in March 2022 in this setting [30].

Immunotherapy in prostate cancer has a limited role in the setting of mCRPC. The only vaccine therapy in prostate cancer to demonstrate an OS benefit thus far is sipuleucel-T, with a median OS of 25.8 versus 21.7 months (HR 0.78, 95% CI, 0.61–0.98), although there was no improvement in PFS or PSA response [31]. This treatment is reserved for asymptomatic or minimally symptomatic mCRPC patients without visceral metastases, and the magnitude of OS benefit was found to be greater in patients with lower baseline PSA [32]. Pembrolizumab, a PD-1 inhibitor, currently carries approvals only for prostate cancer patients with MSI-H and TMB-H disease [33,34]. These approvals were based on tissue-agnostic solid tumor trials that did not have particularly large numbers of prostate cancer patients. Trials of immune checkpoint inhibitors in unselected prostate cancer patients have failed to demonstrate improvements in survival [35–37]. There is currently no indication beyond this biomarker-based population especially given failure of phase III trials that included docetaxel in the mCRPC space (Keynote-921: NCT03834506) and with enzalutamide (Keynote 641: NCT03834493) as well as metastatic hormone-sensitive prostate cancer setting (Keynote-991: NCT04191096).

Therapies targeting the DNA damage repair (DDR) pathways with poly-ADP ribose (PARP) inhibitors have also demonstrated efficacy in selected patients with mCRPC. Olaparib and rucaparib were examined in patients with mCRPC who progressed on prior ARPIs in the phase III, PROfound and phase II, TRITON studies, respectively [38–40]. Olaparib was studied in the phase III PROfound trial with the primary endpoint of investigator-assessed imaging PFS in those who had at least one homologous recombination repair (HRR) mutations that included BRCA1, BRCA2, or ATM and failed prior ARPI in cohort A. Other DDR mutations were included in cohort B. Conversely, the TRITON study required progression on one prior taxane and limited HRR mutations to BRCA1 and BRCA2. Analysis from PROfound demonstrated a PFS and OS benefit in favor of olaparib over ARPI in the BRCA1, BRCA2, and ATM cohort (median OS 19.1 vs. 14.7 months, HR 0.69; 95% CI, 0.50–0.97), while that from TRITON showed antitumor activity in the form of objective responses and PSA response in patients treated with rucaparib. Another PARP inhibitor studied in mCRPC was niraparib in the phase II GALAHAD trial, which included 289 patients of whom overall response rates in the BRCA cohort (n = 79) was 34.2% [41]. Collectively, these aforementioned trials led to the eventual U.S. FDA approval of olaparib in adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone on May 19, 2020. While rucaparib was granted U.S. FDA accelerated approval on May 15, 2020 and niraparib was given a U.S. FDA breakthrough therapy designation on October 4 2019, the approval was reserved only for mCRPC patients with deleterious BRCA mutation (germline and/or somatic) previously treated with ARPI and a taxane-based chemotherapy.

3. Emerging treatment options

There are several treatment candidates with various mechanisms of action being evaluated in prostate cancer. Most involve utilizing prostate-associated antigens and combining these with other forms of treatment. The therapies discussed herein include combination PARPi and oral anti-androgens, radioligands, monoclonal antibodies, small molecules, cell membrane receptors, chimeric antigen receptor T-cell (CAR-T), cytokine-based therapies, and antibody-drug conjugates (ADCs).

As noted above, PARPi are approved for treatment in select mCRPC patients. More recent trials have begun to examine its role in combination with oral anti-androgens in unselected patients. The PROpel study is a phase III study combining abiraterone and olaparib in unselected mCRPC as a first-line treatment [42]. This trial randomized patients to either abiraterone and olaparib or abiraterone and placebo. The primary endpoint of imaging-based progression-free survival (ibPFS) favored the combination group over placebo (24.8 vs. 16.6 months, HR 0.66; 95% CI, 0.54–0.81, p < 0.001). A second study looking at the combination of PARPi with oral anti-androgens in mCRPC is TALAPRO-2. This phase III study randomized patients to enzalutamide plus either talazoparib or placebo in first-line mCRPC [43]. The primary endpoint was the same as in PROpel: ibPFS. The median ibPFS again favored the oral anti-androgen and PARPi combination arm over the anti-androgen and placebo arm (NR vs 21.9 months, HR 0.63; 95% CI, 0.51–0.78; p < 0.001). Importantly, neither study allowed for patients on the placebo arm to receive PARPi at time of progression, a comparison that would mirror a current approach available to selected patients in the United States who progress on abiraterone in the mCRPC setting.

There are many ongoing trials involving 177Lu-PSMA-617 that may expand its role further beyond mCRPC. PSMAfore (NCT04689828) is a phase III trial in taxane-naive mCRPC patients progressing on one line of ARPIs, and who are eligible for a change to a different ARPI [44]. Patients in PSMAfore will be randomized to either treatment with 177Lu-PSMA-617 or an ARPI (abiraterone/enzalutamide) with the primary endpoint for the trial being rPFS. Another trial, PSMAddition (NCT04720157), is evaluating 177Lu-PSMA-617 in mCSPC [45]. This trial will randomize patients to either 177Lu-PSMA-617 added to SOC (defined as ADT+ARPI) versus SOC alone with a primary endpoint of rPFS. A phase 1b trial (PRINCE) investigating the benefits of immunogenic priming with 177Lu-PSMA-617 followed by pembrolizumab in chemotherapy-naive mCRPC patients [46] demonstrated a promising overall response rate of 44% in the 18 patients enrolled and has led to further phase II trial testing (NCT03805594). PSMA-based ligand forms are also being combined with lutetium in phase III clinical trials for patients with mCRPC who have failed prior ARPI but remain chemotherapy naive. The two studies exploring this includes the following studies: SPLASH (NCT04647526) and ECLIPSE (NCT05204927).

Alpha particles are attractive as these deliver high energy with fewer particle tracks to effect cell kill, have a short depth of penetration, and have shorter half-lives, potentially limiting toxicity to normal tissues. Additionally, from a practical perspective, the easier production of alpha particles lends for wider dissemination and use in the clinic [47]. The only alpha emitter approved thus far in prostate cancer is radium 223 dichloride. One alpha emitter being evaluated is actinium-225 (225Ac). A phase I study combining this with a PSMA-localizing antibody, J591, was recently presented by Tagawa et al. (NCT03276572) [48,49]. Thirty-two patients with mCRPC who progressed on at least 1 ARPI and chemotherapy were enrolled in the study. Interestingly, prior treatment with radium 223 and lutetium was allowed, and PSMA PET positivity was not required for enrollment. There was only one patient with dose-limiting toxicity (DLT) at all the planned dose levels: grade 4 anemia and thrombocytopenia. Grade 3 or higher AEs were hematologic. Lower grade AEs included fatigue, pain flare, nausea, and xerostomia (which occurred in 8 patients – 5 previously treated with lutetium – and was limited to grade 1). Clinical data presented included 22 out of 32 patients having any decline in PSA and 12 out of 32 patients experiencing ≥50% PSA reduction (PSA50 response).

CAR-T cell therapy is a new area of therapy being evaluated in prostate cancer. A first-in-human phase I study of PSMA CAR-T by Narayan et al. (NCT03089203) enrolled mCRPC patients and treated them with a PSMA-directed armored CAR-T cell that was modified with a dominant-negative transforming growth factor (TGF)-beta receptor [50]. This study utilized a 3+3 safety design with and without lymphodepletion. Patients were dosed in four cohorts at a range of 10–-30 million cells or 100–300 million cells with or without lymphodepletion. Of the 13 patients treated, 4 had PSA reductions of at least 30%. It must be noted, however, that one of the four patients died in the context of grade 4 cytokine release syndrome (CRS) and sepsis, emphasizing the need for continued vigilance regarding toxicity monitoring. A second phase I study by Dorff et al. (NCT03873805) looked at CAR-T cell therapy targeted to prostate stem cell antigen (PSCA) in mCRPC after at least abiraterone or enzalutamide [51]. Patients were also required to have disease that expressed PSCA as confirmed by City of Hope’s Pathology Department. These CAR-T cells are also using the 4–1BB costimulatory molecule. Four cohorts were planned for treatment with cohort 1 receiving 100 million cells without lymphodepletion chemotherapy. The other three cohorts were planned to receive lymphodepletion first followed by 100 million, 300 million, or 600 million cells per each cohort, respectively. This first-in-human study encountered two DLTs (grade 3 noninfective cystitis and fatigue in both) at a dose of 100 million cells after lymphodepletion chemotherapy. However, upon amendment of the lymphodepletion chemotherapy to reduce the cyclophosphamide portion, no DLTs were encountered in an additional three patients. All three patients treated at the 100 million cell dose level without lymphodepletion progressed, while seven of the nine patients treated at the same cell number but with lymphodepletion had stable disease. The data acquired at this level allowed for escalation to the next dose level of 300 million cells.

Another form of antibody-focused treatment in development utilizes Bi-specific T-cell engagers (BiTEs). An example is pasotuxizumab, which engages CD3 on T-cells and PSMA on prostate cancer cells. A phase I trial enrolled 47 patients with mCRPC post ≥1 taxane and either abiraterone or enzalutamide, and escalated doses of pasotuxizumab in subcutaneous (SC) and continuous intravenous infusion (cIV) routes [52]. It demonstrated activity of the treatment, with dose-dependent PSA reductions. Overall, PSA50 responses occurred in 9 out of 31 (29%) patients in the SC arm and 3 out of 16 (18.8%) in the cIV arm. Common AEs in the SC and cIV arms, respectively, included fever (25/31 [81%] and 15/16 [94%]), injection-site reactions (24/31 [77%] and 0/16 [0%]), chills (7/31 [23%] and 11/16 [69%]), and fatigue (11/31 [36%] and 5/16 [31%]). Despite promising activity, 30 out of 30 evaluable patients developed anti-drug antibodies, prompting development of an improved compound, AMG160 [52,53]. In turn, a phase I trial of AMG160 monotherapy in mCRPC post ≥1 taxane and ARPI enrolled 32 patients treated at 6 dose levels. PSA50 responses occurred in 6 out of 10 patients in dose levels 5 and 6 and 1 out of 18 patients had a RECIST response (at dose level 4). CRS was the most common AE, occurring in 27 out of 32 (84.3%) patients, mostly in the first 2 cycles, presenting with fever, transaminitis, and hypotension. DLTs included rash and GI hemorrhage, both reversible [54]. An example of another BiTE (with its tumor antigen) engaging CD3 on T-cells in mCRPC clinical trials is AMG 509 (STEAP1) (NCT04221542) [55].

Another mode of immunotherapy holding promise is cytokine-based therapies, which may achieve a broader immunologic impact beyond T-cells by having a pleiotropic effect on the tumor microenvironment, including NK cells, myeloid-derived suppressor cells, and tumor-associated macrophages [56]. Clinical application of free cytokines has been largely limited by significant toxicity, which often prevented delivery of effective doses to the tumor [57–60]; however, development of modified cytokines is hoped to improve tumor delivery and reduce toxicity. The multi-arm QuEST1 trial is examining successive cumulative combinations of BNVax (a poxviral-based vaccine against brachyury) and bintrafusp alpha (a novel PD-L1 inhibitor with a TGF-β trap) with N-803 (an IL-15 superagonist) and epacadostat (an indoleamine 2,3 (IDO1) inhibitor). Preliminary results show four out of nine (44%) patients in the BNVax plus bintrafusp alpha and N-803 arm having a PSA reduction by at least 30%, and two out of three (66%) evaluable patients having a radiological response (compared to 1/13 (7.8%) and 0/3, respectively, in the BNVax and bintrafusp alpha only arm), possibly indicating activity of N-803 [61]. NHS-IL12 is an immunocytokine composed of two IL-12 heterodimers fused to an NHS76 antibody that targets exposed DNA in areas of necrosis. A phase I/II trial combining NHS-IL12 with docetaxel in mCSPC and mCRPC is ongoing (NCT04633252) [62]. Preliminary data have established the safety of the combination and the RP2D.

ADCs are another area being explored in prostate cancer. These ADCs include antigen targets, such as six-transmembrane epithelial antigen of prostate 1 (STEAP-1), trophoblast antigen 2 (TROP2), PSMA, and B7 homolog 3 (B7-H3). A phase I trial of an ADC (DSTP3086S) comprising a humanized IgG1 STEAP-1 monoclonal antibody linked to monomethyl-auristatin E was conducted in mCRPC [63]. The 3+3 dose escalation study treated 77 patients. DLTs included transaminitis, hyperglycemia, and hypophosphatemia. Of the 62 patients who were treated at doses >2 mg/kg, 11 (18%) had a PSA50 response. This evidence of antitumor activity complimented the tolerable safety profile in this clinical trial (NCT01283373). Sacituzumab govitecan (a humanized antibody to TROP2 combined with SN-38, the active portion of irinotecan) is being evaluated in a phase II clinical trial of mCRPC patients with progression on abiraterone or enzalutamide (NCT03725761) [64]. This ongoing study will enroll patients at a dose of 10 mg/kg and the primary endpoint will be rPFS. PSMA-focused ADCs include one form, conjugated with monomethyl-auristatin E, which has been tested in the mCRPC setting in a phase II study (NCT01695044) [65]. In this trial, 119 mCRPC patients who had progressed on abiraterone or enzalutamide were treated with the PSMA ADC. PSA50 responses were seen in 14% of all treated patients. Grade 3 AEs that were the most common included fatigue, neuropathy, anemia, neutropenia, and electrolyte imbalance. Another B7-H3 monoclonal antibody, DS-7300, which has a exatecan derivative payload, has been explored in a phase I/II study of advanced solid tumors, including mCRPC (NCT04145622). The mCRPC subset included a heavily pretreated population of 29 patients [66]. No patients had a treatment-emergent AE leading to discontinuation. Besides establishing an RP2D, preliminary results from this study regarding the mCRPC cohort demonstrated 6 patients with partial responses and 15 with stable disease. MGC018, which also targets B7-H3, but has a duocarmycin payload, was studied in a phase I multicohort expansion that included 26 out of 40 patients with prostate cancer [67]. At the last follow-up, 11 out of 22 patients with mCRPC had ≥50% PSA reduction and 4 out of 7 patients had radiographic tumor response and reduction from 13% to 35%.

4. Conclusion

Emerging treatments are moving beyond the mostly androgen-focused regimens that have dominated the approved therapeutic strategies for years. There is a large focus on utilizing more therapies targeted to tumor antigens by exploring rational combinations. As has been practiced in the past, most novel treatments are first evaluated in mCRPC and only brought into earlier disease states if efficacy is proven; however, this need not be the case as long as the risk-to-benefit ratio for use in earlier disease stages can be scientifically justified. New therapeutics bring the promise of expanding options and improving survival for patients in the most advanced stages of disease. There are many practical challenges that can arise in the face of this, and creative strategies will need to be implemented to overcome them.

5. Expert opinion

With a multitude of potential options arising in the armament of prostate cancer therapy, the future of treatment is promising. In light of the current approach to treatment focusing on the androgen receptor, alternative mechanisms of action looking beyond this are crucial to move the field forward. Moreover, in light of a trend of intensification of treatment as an approach to the mCSPC state, having more treatment options may allow for greater latitude in deintensification of existing treatment regimens, consequently allowing for improved quality of life. On the other hand, multiple factors need to be considered regarding the eligibility for treatment intensification for patients with mCSPC including volume of disease (high volume or low volume), risk of disease (high risk vs. low risk), and even use of stereotactic radiotherapy or primary radiotherapy in the prostate area in patients with oligometastatic disease. One of the criteria for triplet therapy, beyond volume or high-risk disease, includes whether patients are considered chemotherapy-fit and likely remain to be the appropriate candidates for intensification therapy. Current trials continue to further elucidate the appropriate population of patients who are deemed to benefit. For instance, further subgroup analysis of the ARASENS trial has shown no major difference between OS outcomes in either high-volume or low-volume disease or in high-risk or low-risk disease, benefiting all equally. However, as with any new treatment, there are challenges that will need to be dealt with. One ongoing challenge is the sequencing of therapies. Treatments with overlapping toxicities or somewhat similar mechanisms comprise many of the currently approved as well as the developing options discussed above. Understanding what appropriate sequence of treatments to maximize survival benefits while optimizing the quality of life will be key to utilizing the treatments in a meaningful way. Additionally, as treatments may share overarching mechanisms, cross-resistance may emerge that could reduce the utility of some of the available options. Sequencing of different treatment options in the mCRPC space includes prioritization of PARPi use over ARPIs or chemotherapy in those who harbor DNA repair gene (DDR) mutations especially BRCA1 and BRCA2. However, there is also emerging benefit in combination therapy with ARPI and PARPi irrespective of DDR mutations given synergistic responses and likely will become approved soon, though not yet as of this writing. Logistical challenges cannot be ignored as was already seen with the issues regarding the use of lutetium in 2022, with ongoing shortage. Utilization of such an agent on a broader scale would require increases in capacity for production; a principle that should be considered with regard to many of the emerging treatments mentioned above [68]. Finally, economic factors which have always been a significant challenge in the implementation of new treatments will be another variable that is important to consider. However, despite advances in therapy for mCRPC, treatment responses lack durability especially when progression ensues. Therefore, a search for other novel therapies with unique mechanism of action and better understanding of mechanisms of resistance to newer treatment options such as lutetium must be sought.

Article highlights.

• The treatment landscape for metastatic hormone-sensitive prostate cancer has rapidly evolved with androgen deprivation therapy as backbone and additional androgen-receptor pathway inhibitors (ARPI) or docetaxel or combination as triplet therapy as first-line treatment.

• Treatment sequencing in metastatic castrate-resistant prostate cancer (mCRPC) remains an important issue upon failure from hormone-based therapies.

• Lutetium has recently been approved for mCRPC after failure from one ARPI and docetaxel, with improvements seen in radiographic progression-free survival and overall survival.

• Emerging treatment options include radioactive ligand, antibody-drug conjugates, chimeric antigen receptor T-cell, and cytokine-based therapies.